Joint Canadian Association of Gastroenterology and Crohn’s Colitis Canada Position

Statement on Biosimilars for the Treatment of Inflammatory Bowel Disease.

Paul Moayyedi1, Eric I. Benchimol2,3, David Armstrong1, Cathy Yuan1, Aida Fernandes1,

Grigorios I. Leontiadis1.

1. Division of Gastroenterology and Farncombe Family Digestive Health Research

Institute, McMaster University, Hamilton, Ontario, Canada

2. Children’s Hospital of Eastern Ontario (CHEO) Inflammatory Bowel Disease Centre,

Division of Gastroenterology, Hepatology and Nutrition and CHEO Research Institute,

Ottawa, Ontario, Canada

3. Department of Pediatrics and School of Epidemiology and Public Health, University of

Ottawa, Ottawa, Ontario, Canada.

Correspondence: Paul Moayyedi BSc MB ChB PhD MPH FRCP FRCPC AGAF, FACG

Audrey Campbell Chair of Ulcerative Colitis Research

1280 Main St. W. HSC 3V3

Hamilton, ON Canada, L8S 4K1

Introduction

The development of anti-tumour necrosis factor (TNF) therapies has transformed the care of

patients with immune-mediated diseases such as inflammatory bowel disease (IBD), including

ulcerative colitis and Crohn’s disease, psoriasis and inflammatory arthropathies, including

rheumatoid arthritis and ankylosing spondylitis. For IBD patients, these biologic therapies are

effective at inducing and maintaining remission (1), reducing the need for surgery (2) and

improving quality of life (3). Although anti-TNF therapies are effective in several different

immune-mediated disorders, individual biologics are not, necessarily, equally effective in all

disorders suggesting that their actions may differ between disorders. For example, the paradox

that anti-TNF drugs used to treat rheumatoid arthritis (RA) and psoriasis may yet cause joint

pains and skin reactions in IBD patients, emphasises our imperfect understanding of the

mechanism of action of these biologic therapies and the need to evaluate treatment outcomes

separately for different disorders.

The main factors that limit the use of anti-TNF drugs are adverse events and cost. Anti- TNF

therapy is associated with joint pains, dermatological disorders and transfusion reactions (4).

Transfusion reactions are associated with the development of antibodies to anti-TNF agents and

this may also be associated with reduced treatment efficacy (5). Anti-TNF agents are also

associated with an increased risk of infection (6) and risk of lymphoma although these risks may

be exacerbated, to a greater or lesser extent, by the concomitant use of azathioprine or other

immunosuppressive agents (7).

Anti-TNF therapies are also expensive costing up to $20,000 per year for each patient in Canada.

Canada spent more on biologic therapies for all indications than on any other class of drug in

2018 accounting for 8.2% of the $33.7 billion spent on prescription medications (8). Whilst the

cost of these therapies is significant, the cost of having IBD is also expensive to society. It is

estimated that the indirect cost of IBD was $1.29 billion in Canada in 2018 (9, 10). Anti-TNF

therapies can improve quality of life and productivity and, accounting for these societal costs,

biologics may offer value for money (11). In the Canadian setting, health care is mainly funded

centrally by the tax payer and the government, understandably, focuses on how biologic therapy

may reduce health care costs. This is less clear cut with research using health administrative data

failing to demonstrate any significant decrease in hospitalizations or surgical resections in the

anti-TNF era compared to what would be expected if these drugs had not been introduced (12).

Given this perspective it is understandable that approaches to reducing the cost of these drugs are

being explored.

The emergence of biosimilars, also known as subsequent entry biologics have provided an

opportunity for third party payers to reduce anti-TNF therapy drug costs. A biosimilar is a

biological medical product that is similar to the original but manufactured by a different

company once the patent for that product has expired. They are typically less expensive than the

original product and therefore an obvious target in attempts to reduce biologic drug costs.

Biosimilars are distinct from usual generic drugs, which are simple small molecules that are

relatively straightforward to reproduce and manufacture on a large scale, and identical to the

original drug. Biologic therapies are more complex proteins and require replication in living

cells. The product is dependent on the type of genetically modified cell being used, the

production process and purification techniques (13). The manufacturing process is considerably

more expensive than standard small molecules and therefore costs of biosimilars are higher than

generically produced drugs. Furthermore, the variation from the originator is greater than would

normally be seen with generics. However, it is important to emphasize that even with the original

manufacturer there is potential for variability between each manufacturing run due to the

complexity of living organisms. The Federal Drug Agency has released documents regarding the

approval process for biosimilars (14) that other regulatory authorities have largely adopted (15).

Essentially biosimilars must show a high degree of similarity to the original product and have no

clinically meaningful differences in safety, purity and potency (14). This is a reasonable

definition in principle but the definitions of “high degree of similarity” as well as “clinically

meaningful differences in safety and potency” need further clarification in clinical practice.

The Canadian Association of Gastroenterology has previously published a position statement on

biosimilars (16) but this was six years ago, and more data are now available. Crohn’s and Colitis

Canada has published a position statement more recently (17) but the two organizations felt it

was of value to release a joint position statement after a full literature review. Several positions

statements have been released by various organizations (Table 1) but none has provided an

explicit literature search, nor have they assessed the quality of evidence of a defined clinical

question according to GRADE criteria (18).

This position statement will focus on the data available for the comparison of anti-TNF therapies

with their biosimilars as these are the only biosimilars that are currently approved in Canada for

IBD. The issues raised in this document are likely to apply to other biologics. The search

strategy developed to identify relevant papers for the position statement is given in Appendix 1.

There are a number of systematic reviews on this topic (19-25), however except for one paper

(25), they rely on case series of IBD patients starting a biosimilar or switching to a biosimilar

with no comparison to those that are prescribed the originator, so are difficult to interpret. We

focused on evidence from randomized controlled trials or cohort studies that compared the

biosimilar with the originator. The endpoints we focused on were efficacy, safety and also

acceptance by the patient. Although there are randomized, controlled clinical trials comparing

originator biologics and biosimilars for the management of rheumatoid arthritis, spondylitis and

psoriasis (26-30), we restricted the search to IBD as the efficacy and safety of biosimilars may be

different in different diseases. We assessed biosimilars compared to the originator in IBD

patients naïve to either agent as well as evaluating data relating to switching patients already on

an anti-TNF drug to a biosimilar. The reason for this categorization is that when switching drug

there is also the added issue of patient intolerance due to a nocebo effect (31).

Biosimilar versus originator treatment in IBD patients naïve to anti-TNF therapy

We identified one randomized controlled trial (32) that compared the biosimilar CT-P13 with

originator infliximab in 220 Crohn’s disease patients who had active disease despite non-biologic

therapy. This was a non-inferiority trial with a sample size that had 85% power for a non-

inferiority margin of -20%. The primary endpoint was a 70-point decrease in Crohn’s Disease

Activity Index (CDAI) at week 6 but the trial was continued for one year. Patients were

randomized 1:1:1:1 with patients in two groups continuing on CT-P13 or infliximab throughout

the year whilst those in the other two groups were switched to the other medication at week 30,

continuing the alternate medication (CT-P13 or originator) for the rest of the year. GRADE

evaluation of this trial identified a low risk of bias. At week 6, 69% of the biosimilar group

were in remission compared with 74% of the originator infliximab group (5% difference; 95%

confidence intervals (CI) 17% in favour of originator infliximab to 7% in favour of CT-P13). At

week 30 clinical remission was seen in 55% of the CT-P13 group compared to 57% of the

originator infliximab group (-2%; 95% CI = -15% to +12%). At week 30 there were 6 (5%)

treatment related serious adverse events in the CT-P13 group compared with 9 (8%) in the

originator infliximab group. Neutralizing antibodies were similar in the CT-P13 (22 (20%)) and

originator infliximab (21 (19%)) groups at week 30. There was one additional biosimilar

randomized trial (33), but this did not inform the question of interest as it compared intravenous

with subcutaneous CT-P13 and there was no originator comparator.

We identified one cohort study (34) that compared biosimilars with originator infliximab in 5050

Crohn’s patients that were infliximab naïve. This study used the Système National des Données

de Santé French nationwide health administrative database and the primary outcome was a

composite endpoint comprising of death, Crohn’s disease related surgery, all cause

hospitalization and switch to another biologic therapy. There were 2499 patients in the CT-P13

group compared with 2551 in the originator infliximab group, studied from 2015 to end of June

2017. There was no difference between the two groups for the primary outcome (hazard ratio

(HR) in favour of CT-P13 = 0.92; 95% CI = 0.85 to 0.99). There was no difference between the

two groups in terms of Crohn’s disease hospitalization (HR = 1.00; 95% CI = 0.90 to 1.11) or

surgery (HR = 1.09; 95% CI = 0.92 to 1.28) or switch to another biologic (HR = 0.93; 0.79 to

1.08). There was also no difference between the groups for serious infections (HR = 0.82; 95%

CI = 0.61 to 1.11), tuberculosis (HR = 1.10; 95% CI = 0.36 to 3.34) and solid or hematologic

malignancy (HR = 0.66; 95% CI = 0.33 to 1.32). The groups were well balanced for age and sex

as well as disease duration and previous medications. However, treatment duration was different

given that 65% of the originator infliximab group commenced the drug in 2015 compared with

only 28% of the CT-P13 group. The originator infliximab group may therefore have had longer

to accrue treatment failure and adverse events, and this may have biased the results in favour of

the biosimilar. In addition, treatment strategies have changed over time, such as more recent

emphasis on a treat-to-target strategy, which would also favour the biosimilar.

The quality of evidence for starting an infliximab naïve patient with active Crohn’s disease on

CT-P13 rather than originator infliximab to induce and maintain remission is low according to

GRADE criteria (Table 2). The evidence from the cohort study is low and evidence from the

randomized trial is downgraded two points for imprecision given that the number of patients

evaluated is modest and it is plausible within the 95% confidence intervals of these data that

originator infliximab results in a 15% increased remission rate compared to the biosimilar. The

quality of evidence for active ulcerative colitis is very low according to GRADE criteria as there

are no comparative cohort studies or randomized trials in this disease group, so the data are

indirect and relate to the evidence from Crohn’s disease. The evidence for equivalence in safety

between CT-P13 and originator infliximab was very low according to GRADE criteria. This

mainly relies on one cohort study with a limited number of adverse events (Table 2). There are

no data for any anti-TNF biosimilars other than infliximab.

In the future there needs to be randomized controlled trials in ulcerative colitis patients and it is

important that cohort studies compare the biosimilar with patients on the originator biologic as

without this comparator it is not possible to understand which intervention is the most effective

and safe.

Non-medical switch from originator to biosimilar anti-TNF therapy in IBD patients

We identified two randomized controlled trials (35, 36) in 448 IBD patients that were in

remission on infliximab for at least 3 (36) to 6 (35) months who were randomized to either

continuing on the originator or switching to the biosimilar CT-P13. Both trials followed patients

for one year and one trial (35) was low risk of bias whereas the other (36) had unclear method of

randomization or concealment of allocation. One trial (35) evaluated patients on biologics for all

indications but data on ulcerative colitis and Crohn’s disease could be assessed separately from

the information given in the paper and supplementary appendix. Overall intention to treat (ITT)

remission rates were similar between the two groups with relative risk of not being in remission

at one year with infliximab originator = 0.89 (95% CI = 0.58 to 1.38) (Figure 1). There was

some heterogeneity between results with an I2 of 54% (suggesting that 54% of the variation

between the studies was unexplained by chance). However, the ITT loss of response or

worsening disease rates were lower with the originator infliximab compared to the biosimilar

(relative risk of loss of response/worsening disease = 0.64; 95% CI = 0.44 to 0.94) (Figure 2).

There was no heterogeneity between trials with an I2 of 0%. The number needed to harm was 11

(95% CI = 6 to 50). One trial (36) only reported data for Crohn’s disease and ulcerative colitis

combined whereas the diseases were analysed separately in the other trial (35). This trial (35)

suggested that worsening of disease was seen more often with Crohn’s disease (per protocol

worsening = -14.3% difference (95% CI = -29.3% to 0.7% in favour of infliximab originator)

than with ulcerative colitis (per protocol worsening = -2.6% difference (95% CI = -15.2% to

10.0% in favour of infliximab originator).

Neither randomized trial (35, 36) reported safety data specific to IBD patients. One trial (36) did

not report on adverse events and the other only gave adverse events for all patients in the trial

and therefore included patients with rheumatoid arthritis, ankylosing spondylitis and psoriasis as

well as IBD. Serious adverse events were similar between the infliximab originator (24 of 241

(10%) patients) and the CT-P13 (21 of 241 (9%) patients) groups as were overall adverse events

(70% versus 68%) and events leading to discontinuation of the drug (4% versus 3%).

We identified two cohort studies (37, 38) that assessed 293 IBD patients receiving originator

infliximab; overall, 151 patients who continued the originator were compared to 142 patients

who switched to the biosimilar (CT-P13). An additional cohort study (39) evaluated patients on

infliximab for all indications but did not report results specifically for IBD patients. One of the

IBD cohort studies (37) evaluated pediatric patients who either continued on originator

infliximab or switched to CT-P13. There was no difference in corticosteroid-free remission rates

(defined clinically) without the need for dose intensification; remission was reported in 28/36

(78%) of infliximab continued group and 30/38 (79%) of the CT-P13 switch group (relative risk

= 0.99; 95% CI = 0.78 to 1.25). The other IBD cohort study (38) evaluated 219 adults with IBD

(120 with Crohn’s disease and 99 with ulcerative colitis) and followed them for one year,

evaluating every 4 months with biological markers, the Harvey Bradshaw Index (HBI) for

Crohn’s disease, and the partial Mayo Score (PMS) for ulcerative colitis. This primary endpoint

was disease worsening defined as increase in HBI ≥ 4 or PMS ≥ 5 from baseline. Disease

worsening occurred in 8/115 (7%) in the infliximab originator group compared to 11/104

(10.5%) in the CT-P13 switch group (relative risk = 0.66; 95% CI = 0.28 to 1.57). Similarly, the

proportion who required biologic dose increase or treatment discontinuation was 16/115 (14%)

in the infliximab originator group compared to 22/104 (21%) in the CT-P13 group (relative risk

= 0.69; 95% CI = 0.38 to 1.25). Both studies were underpowered and open to bias as the

decision to switch was made by the patient and clinician. Nevertheless, the results are similar to

the randomized controlled trials in that there was no difference in remission rates but there was a

suggestion of a greater proportion of CT-P13 switch patients who deteriorated, lost response or

needed a change in therapy compared with those continued originator infliximab therapy. This is

supported by another cohort study (39) evaluating all patients on biologic therapy, regardless of

indication. This study reported on 1388 patients who continued originator infliximab therapy

with 136 patients who switched to CT-P13. Patients who switched to CT-P13 were more likely

to discontinue treatment (hazard ratio = 5.53; 95% CI = 4.01 to 7.63) compared to those who

continued with originator infliximab therapy for 12 months.

Both cohort studies reported adverse events, one reporting all adverse events (37) and the other

reporting serious adverse events (38). Both studies found no difference in adverse events

between groups and the overall relative risk of adverse events in the infliximab originator group

was 0.94 (95% CI = 0.74 to 1.21) (Figure 3). The cohort study (39) assessing those on

infliximab for all indications also found no difference in adverse events between those

continuing on infliximab originator compared to CT-P13 (adjusted incidence ratio = 0.67; 95%

CI = 0.19 to 2.30).

In summary, the evidence is against switching from originator infliximab to CT-P13 in IBD

patients who are doing well on the original drug. This is very low quality evidence according to

GRADE criteria based on randomized trial evidence that patients on CT-P13 have a higher risk

of worsening of disease and need to dose escalate or switch (Table 3). The evidence was

downgraded as one study had unclear risk of bias and it was downgraded two further levels for

imprecision. There is evidence that both drugs have a similar safety profile, but this is again

very low quality evidence according to GRADE criteria (Table 3).

Future studies should focus on comparative cohort studies comparing the originator biologic with

its biosimilar and not simply providing information on experience with the biosimilar. Without

comparative data it is not possible to reach evidence-based conclusions.

Cost-effectiveness of using biosimilars compared to the originator anti-TNF

The Canadian cost of originator infliximab (Remicade) is $4,471 CAD compared with $1,934

CAD for CT-P13 (Inflectra) per claim. These costs are derived from aggregate claims data from

the National Prescription Drug Utilization Information System (40). This source does not

include undisclosed discounts and rebates that are in place for both products and so actual costs

are difficult to determine as there are no publicly-available data of the actual cost to the payer.

We identified one health economic model (41) that compared infliximab originator versus the

biosimilar for active Crohn’s disease using UK costs over a one year time frame. This model

found biosimilar therapy would be more cost-effective approximately 85% of the time in a

probabilistic analysis based on the model’s assumptions that £30,000 per quality adjusted life

year gained was the threshold for cost-effectiveness. This model only evaluated biologic-naïve

patients started on infliximab originator or the biosimilar and assumed that both were equally

effective with no uncertainty in the model for efficacy. The main area of uncertainty addressed

in the model was differences in anti-drug antibody development. Whilst this is one area of

uncertainty there are others and in particular the model could have used the -2% (95% CI = -15%

to +12%) difference in efficacy from the randomized trial in biologic naïve Crohn’s disease

patients.

We did not identify any health economic models that evaluated switching to a biosimilar in IBD

patients who achieved remission on the originator biologic. However, one cohort study (38)

evaluated health care costs in those remaining on infliximab originator for any indication versus

those switched to CT-P13. This Turkish cohort study (39) found that those remaining on the

originator cost less than those switching to CT-P13 (average total health care costs = 2,009

Turkish Lira per patient in the CT-P13 group compared to 1,640 Turkish Lira in the originator

group, p=0.046). This is consistent with a systematic review (42) of non-medical switching of

all types of drugs on economic outcomes which found that, despite the generic being cheaper,

overall health care costs increased in 69% of studies and were neutral in 31% with no study

reporting a cost saving (42).

Recommendations

We suggest that an infliximab biosimilar may be started in patients with active Crohn’s disease

who are naïve to anti-TNF therapy rather than starting with the infliximab originator. This is a

weak recommendation based on low quality evidence and depends on the price differential of the

two drugs. If the price differential is modest, then the infliximab originator should be used.

However, if the price differential is comparable to that calculated based on the current, published

list price of the drugs, it is plausible that the biosimilar is more cost-effective. The weak

recommendation implies that the clinician should discuss risks and benefits carefully with the

patient, taking into account the preference of the patient, and decisions should be made on a

case-by-case basis. There are insufficient data to recommend the use of biosimilars in patients

with active ulcerative colitis naïve to infliximab.

We recommend against non-medical switching from originator infliximab to biosimilar in

patients who have stable IBD and are doing well on the original product. This is a weak

recommendation based on very low quality evidence but data suggest that switching in this

setting leads to an increased risk of worsening of disease, dose escalation and/or switching to an

alternative therapy.

We do not recommend automatic substitution of biologic with a biosimilar in IBD patients given

the paucity of evidence for the efficacy and safety of this approach.

Conflicts of interest

PM, EIB, CY, AF and GIL declared that, over the last 2 years, they had no conflicts relevant to

the topics of this Position Statement.

DA declared that, over the last 2 years, he received honoraria from Takeda (a pharmaceutical

company producing biologics) for participating in advisory boards that discussed vedolizumab

and teduglutide, neither of which was related to the topics of this Position Statement

(vedolizumab is not an anti-TNF biologic and, furthermore, it is protected by patents such that no

relevant biosimilars can be produced currently; teduglutide is not a biologic), and that he

received a research grant from ABBVIE (a pharmaceutical company producing biologics) for an

investigator-initiated study (“Inflammation-related differences in mucosa-associated microbiota

and intestinal barrier function in colonic Crohn’s disease”) that is not related to the topics of this

Position Statement.

PM is Nominated Principle Applicant, AF is Executive Director and all authors are involved

with the “Inflammation, Microbiome, and Alimentation: Gastro-Intestinal and Neuropsychiatric

Effects: the IMAGINE network” - a Strategy for Patient-Oriented Research CIHR Chronic

Disease Network. The research conducted by this network has no hypothesis that is directly

related to biologics other than evaluation of how the microbiome and diet may allow more

precise targeting of patients with inflammatory bowel disease who are likely to respond to

treatment.

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Table 1. Position statements reached by other groups on the use of biosimilars

Group Year Use in naïve patients

Switch for those already on originator

Automatic substitution

CAG 2013 Await studies No No ECCO 2013 Await studies No No Spanish Society of Gastroenterology

2013 Yes No No

Polish National Consultant in Gastroenterology

2014 Yes No No

Italian IBD group 2014 Yes Await studies No British Society of Gastroenterology

2015 Yes Yes No

NHS Wales 2015 Yes (patient doctor choice)

Yes (patient doctor choice)

No

ESPGHAN 2015 Yes No No Belgian IBD Research Group

2015 Yes No No

OAG 2016 No No No ESPGHAN 2019 Yes Yes No Crohn’s and Colitis Foundation

2019 Yes Yes (patient doctor choice)

No

CCC 2019 Yes Yes (patient doctor choice)

No

BC Pharmacare 2019 Yes Yes Yes NHS = national health service ESPGHAN = European Society for Pediatric Gastroenterology Hepatology and Nutrition IBD = inflammatory bowel disease ECCO – European Crohn’s and Colitis Organization OAG = Ontario Gastroenterology Association CAG = Canadian Gastroenterology Association CCC = Crohn’s Colitis Canada BC = British Columbia

Table 2 CT-P13 compared to infliximab originator for active Crohn's disease naïve to anti-TNF therapy: summary of findings table

Certainty assessment № of patients Effect

Certainty Importance № of

studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations CT-P13 infliximab originator

Relative (95% CI)

Absolute (95% CI)

Crohn's disease remission (follow up: mean 6 weeks; assessed with: A reduction of CDAI > 70 points)

1 randomised trials

not serious not serious not serious very serious a none 77/111 (69.4%) 81/109 (74.3%) RR 0.96 (0.76 to 1.22)

30 fewer per 1,000 (from 178 fewer to

163 more)

⨁⨁◯◯ LOW

CRITICAL

Switch to another biologic (follow up: mean 12 months; assessed with: Switch of drug in administrative database)

1 observational studies

very serious b not serious not serious not serious none 312/2499 (12.5%)

406/2551 (15.9%)

HR 0.93 (0.79 to 1.08)

10 fewer per 1,000 (from 31

fewer to 12 more)

⨁⨁◯◯ LOW

CRITICAL

Serious infections (follow up: mean 12 months; assessed with: Administrative database)

1 observational studies

serious b not serious not serious serious c none 83/2499 (3.3%) 115/2551 (4.5%) HR 0.82 (0.61 to 1.11)

8 fewer per 1,000

(from 17 fewer to 5

more)

⨁⨁◯◯ LOW

CRITICAL

CI: Confidence interval; RR: Risk ratio; HR: Hazard Ratio

Explanations

a. Possibility that CT-P13 is up to 15% less effective than infliximab originator. This was felt to be an important difference when substituting one drug for a similar drug b. Decision to use CT-P13 was up to patient and clinician. c. 95% CI include important differences in safety

Table 3 Non-medical switching to CT-P13 compared to continuing on infliximab originator for stable IBD on originator infliximab: summary of findings table

Certainty assessment № of patients Effect

Certainty Importance № of

studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations CT-P13 infliximab originator

Relative (95% CI)

Absolute (95% CI)

Not in remission (follow up: mean 12 months; assessed with: Defined clinically)

2 randomised trials

serious a not serious not serious serious b none 73/234 (31.2%) 59/214 (27.6%) RR 0.89 (0.58 to 1.38)

30 fewer per 1,000 (from 116 fewer to

105 more)

⨁⨁◯◯ LOW

CRITICAL

loss of response or worsening of disease (follow up: mean 12 months; assessed with: clinical opinion)

2 randomised trials

serious a not serious serious c serious b none 57/234 (24.4%) 33/214 (15.4%) RR 0.64 (0.44 to 0.94)

56 fewer per 1,000 (from 86

fewer to 9 fewer)

⨁◯◯◯ VERY LOW

CRITICAL

Adverse events (follow up: mean 12 months; assessed with: Assessed clinically (either all adverse events or serious adverse events))

2 observational studies

serious d not serious serious c serious b none 33/142 (23.2%) 29/151 (19.2%) RR 0.94 (0.74 to 1.21)

12 fewer per 1,000 (from 50

fewer to 40 more)

⨁◯◯◯ VERY LOW

CRITICAL

CI: Confidence interval; RR: Risk ratio

Explanations

a. One of the two trials had an unclear risk of bias b. 95% CI wide with number of events < 250 c. Each trial defined loss of response differently d. Two observational studies where decision to switch to CT-P13 is up to patient and clinician

Figure 1. Randomized controlled trials of switch to a biosimilar compared to continuing

with originator infliximab in inflammatory bowel disease patients: proportion not in

remission at one year

Figure 2. Randomized controlled trials of switch to a biosimilar compared to continuing

with originator infliximab in inflammatory bowel disease patients: proportion with loss of

response or worsening disease

Figure 3. Adverse events in cohort studies of switch to a biosimilar compared to continuing

with originator infliximab in inflammatory bowel disease patients

Appendix: Search strategy.

Database: OVID Medline Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) 1946 to Present, Embase <1974 to 2019 October 08>, EBM Reviews - Cochrane Central Register of Controlled Trials <September 2019>, EBM Reviews - Cochrane Database of Systematic Reviews <2005 to October 3, 2019> Search Strategy: -------------------------------------------------------------------------------- 1 (inflammatory bowel disease* or ulcerative colitis or Crohn* or IBD).tw,kw. (260985) 2 exp Biosimilar Pharmaceuticals/ (5959) 3 exp biosimilar agent/ (4133) 4 (biosimilar* or inflectra).tw,kw. (10755) 5 (biologic* adj3 (follow-on or subsequent entry or similar)).tw,kw. (9120) 6 or/2-5 (20290) 7 1 and 6 (1358) 8 randomized controlled trial.pt. (971168) 9 clinical trial.pt. (797929) 10 random*.mp. (3989679) 11 placebo.ab. (752778) 12 drug therapy.fs. (5781246) 13 (placebo: or double-blind:).mp. (1248843) 14 clinical trial:.mp. (3082388) 15 blind:.tw. (997409) 16 or/8-15 (10559041) 17 7 and 16 (891) 18 controlled study/ or major clinical study/ (8856293) 19 comparative study/ or (comparative or comparison or compared or controlled).tw. (13227283) 20 exp cohort analysis/ or exp Cohort Studies/ (2569068) 21 (cohort or cohorts).tw,kw. (1522008) 22 prospective*.tw,kw. (1882262) 23 (followed or follow up).tw. (4564759) 24 exp longitudinal study/ or exp Longitudinal Studies/ (395029) 25 (longitudinal or time series).tw. (614437) 26 ((evaluat* or multicenter) adj3 (studies or study)).tw. (1373139) 27 ((population or hospital) adj based).tw. (352933) 28 (trial or groups).ab. (6264896)

29 or/18-28 (25200684) 30 7 and 29 (950) 31 17 or 30 (1227) 32 (exp animals/ or exp animal/ or exp nonhuman/ or exp animal experiment/ or animal model/ or animal tissue/ or non human/ or (rat or rats or mice or mouse or swine or porcine or murine or sheep or lambs or pigs or piglets or rabbit or rabbits or cat or cats or dog or dogs or cattle or bovine or monkey or monkeys or trout or marmoset$).ti.) not (humans/ or human/ or human experiment/ or (human* or men or women or patients or subjects).tw.) (10170739) 33 31 not 32 (1224) 34 remove duplicates from 33 (867) 35 limit 34 to english language [Limit not valid in CDSR; records were retained] (847) ***************************